Low-dose methotrexate does not act on IL-1β, IL-6 and CRP and did not lower CV events in stable CAD
AHA 2018 – Chicago, IL, USA
The Cardiovascular Inflammation Reduction Trial (CIRT): Low Dose Methotrexate for the Prevention of Atherosclerotic Events
Presented at the AHA congress 2018 by: Paul Ridker (Boston, MA, USA)
Introduction and methods
Patients with rheumatoid arthritis (RA) and those with atherosclerosis share a commonality, namely a chronically inflamed state. In inflammation, IL-1β, the NLRP3 inflammasome, and more downstream IL-6, are central in the pathway that results in C-reactive protein production (CRP). This pathway induces a variety of signals that increase inflammation.
Two studies assessing the effect of reducing inflammation on CV events were conducted in parallel: the industry-funded CANTOS trial evaluating the IL-1β inhibitor canakinumab and the public money (NIHBL)-funded CIRT trial evaluating low-dose methotrexate. The CANTOS trial provided proof-of-principle on the effect of lowering inflammation via lowering IL-1β and IL-6, which yielded 15-17% reduction of MACE and MACE+. The Cardiovascular Inflammation Reduction Trial (CIRT) set out to address whether inflammation reduction with low-dose methotrexate (LD-MTX), in the absence of lipid lowering, can reduce cardiovascular event rates.
LD-MTX is inexpensive, but its biology with respect to the IL-1β to IL-6 to CRP pathway is unknown. It is used as a first line therapy for RA and psoriatic arthritis, and it is associated with a good safety record, based on over 40 years of use in older individuals with similar co-morbidities as those who have suffered a heart attack. Observational, non-randomized evidence suggests a reduction in vascular events among patients with RA and psoriasis who are treated with LD-MTX.
To elucidate this further, the randomized CIRT trial was conducted in patients with stable CAD (history of MI or multivessel CAD, well-treated), with persistent evidence of inflammation (type 2 diabetes or metabolic syndrome). Patients were randomized to LD-MTX 15-20 mg po once weekly plus daily folate 1 mg (titrated based on an algorithm based on labs and symptoms) or to LD-MTX placebo po once weekly plus folate 1 mg. The primary endpoints were MACE (MI, stroke, CV death), MACE+ (MACE plus hospitalization for unstable angina requiring urgent revascularization) and CV death. 4786 adult patients were randomized in 417 US and Candadian sites. Only 10 patients were lost to follow-up. Baseline LDL-c was 68.0 mg/dL, and hsCRP was 1.5 mg/L.
- LD-MTX resulted in significant increases in ALT, AST and MCV and significant reduction in white blood cell count, hematocrit and hemoglobin levels.
- LD-MTX had no clinically relevant effect on LDL-c, HDL-c and triglyceride levels.
- LD-MTX had no statistically significant effect on IL-1β, IL-6 and CRP.
- LD-MTX did not significantly affect the primary outcome of MACE (incidence rate per 100 person-years: 3.46 with LD-MTX vs. 3.43 with placebo, HR: 1.01, 95%CI: 0.82-1.25, P=0.91).
- LD-MTX did not significantly affect MACE+ (4.13 vs. 4.31 per 100 person-years, HR: 0.96, 95%CI: 0.79-1.16, P=0.67).
- LD-MTX did not show a significant effect on the secondary outcomes of all-cause mortality (HR: 1.16, P=0.32), hospitalization for heart failure (HR: 0.95, P=0.95) and MACE or revascularization (HR: 0.95, P=0.57), nor on tertiary outcomes.
- Safety of LD-MTX was quite good, with no significant increase in serious adverse events (13.5% vs. 13.0%, P=0.52). An unanticipated increase in non-basal cell malignancies was with LD-MTX (0.65 vs. 0.24%, P=0.0026).
Given the positive findings of CANTOS and the neutral findings of CIRT, inhibition of the IL-1β to IL-6 to CRP pathway of innate immunity appears to be important for atheroprotection, irrespective of lipid-lowering. The results of these two trials point toward future work targeting upstream inhibition of the NLRP3 inflammasome, or downstream inhibition of IL-6 as potential targets for novel CV therapeutics. Prof. Ridker concluded that this represents a neutral, but very informative study.
Sidney Smith, the discussant of the CIRT trial, noted that psoriasis patients have a high risk of CV events, and that in them, LD-MTX seemed to reduce events. Psoriasis is a state of chronic inflammation. In the mechanism of inflammation, cholesterol clusters are an important stimulant in activating the pathway. In the CIRT trial, the mean LDL-c levels was 68 mg/dL, thus patients were well-treated. In CANTOS, mean LDL-c was 86 mg/dL. hsCRP was also lower in CIRT as compared to CANTOS. Thus, patients in CIRT were at lower risk than those in CANTOS. In CANTOS, a lower level of IL-1β was seen, which was associated with a reduction in IL-6, hsCRP and MACE. These effects were not observed in CIRT.
Smith considered these interesting observations on selective drug effects. It will be interesting to see the results of the LoDoCo study, which evaluates colchicine, an agent that also acts on IL-1β.
He noted that these results are another testimony of the value of RCTs and of the limitations of observational and animal data in determining the efficacy of drug interventions on patient outcomes.
- Our reporting is based on the information provided at the AHA Scientific Sessions -